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Cooperativity between the orthosteric and allosteric ligand binding sites of RORγt

DOI: 10.1073/pnas.2021287118 DOI Help

Authors: Rens M. J. M. De Vries (Technische Universiteit Eindhoven) , Femke A. Meijer (Technische Universiteit Eindhoven) , Richard G. Doveston (Technische Universiteit Eindhoven; University of Leicester) , Iris A. Leijten-Van De Gevel (Technische Universiteit Eindhoven) , Luc Brunsveld (Technische Universiteit Eindhoven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 118

State: Published (Approved)
Published: February 2021
Diamond Proposal Number(s): 19800

Abstract: Cooperative ligand binding is an important phenomenon in biological systems where ligand binding influences the binding of another ligand at an alternative site of the protein via an intramolecular network of interactions. The underlying mechanisms behind cooperative binding remain poorly understood, primarily due to the lack of structural data of these ternary complexes. Using time-resolved fluorescence resonance energy transfer (TR-FRET) studies, we show that cooperative ligand binding occurs for RORγt, a nuclear receptor associated with the pathogenesis of autoimmune diseases. To provide the crucial structural insights, we solved 12 crystal structures of RORγt simultaneously bound to various orthosteric and allosteric ligands. The presence of the orthosteric ligand induces a clamping motion of the allosteric pocket via helices 4 to 5. Additional molecular dynamics simulations revealed the unusual mechanism behind this clamping motion, with Ala355 shifting between helix 4 and 5. The orthosteric RORγt agonists regulate the conformation of Ala355, thereby stabilizing the conformation of the allosteric pocket and cooperatively enhancing the affinity of the allosteric inverse agonists.

Journal Keywords: nuclear receptors; RORγ; tallosteric modulators; structure elucidation; drug discovery

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I03-Macromolecular Crystallography

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)